1. Field of the Invention
The present invention relates to a time-of-flight mass spectrometer with which mass spectrometry is performed by ionizing at least part of a sample to be measured and by measuring the time of flight of ions.
2. Description of the Related Art
Recently, imaging mass spectrometry has been attracting attention as a technology for measuring the distribution of substances on the surface of a sample in such fields as pathology research and development of new pharmaceuticals. In an imaging mass spectrometry technology, mass spectrometry is performed on the surface of a sample and a two-dimensional distribution of detection intensity corresponding to the mass-to-charge ratios of the substances is obtained, and thereby information regarding the distribution of the substances in the sample surface is obtained. With imaging mass spectrometry, biological molecules such as protein and drug molecules can be identified and, furthermore, the spatial distribution of these molecules can be measured with high spatial resolution.
In general, mass spectrometry is a method in which a spectrum that includes the mass-to-charge ratios and the detection intensities of an ionized sample is obtained by being irradiated with laser light, ions, electrons, or the like so as to separate the sample in terms of the mass-to-charge ratios.
Examples of measures used to generate ions from a sample include laser beams and charged particle beams such as ion beams. These beams are generally referred to as primary beams. When an ion beam is used as the primary beam (primary ion beam), generated ions are referred to as secondary ions. Examples of known methods in which a laser is used as the primary beam include a matrix-assisted laser desorption/ionization (MALDI) method, in which a sample mixed with a matrix and crystallized is ionized by being irradiated with a pulsed and tightly converged laser beam, and a secondary ion mass spectrometry (SIMS) method, in which a sample is ionized by being irradiated with a primary ion beam.
In many cases, a time-of-flight method is adopted as a method of separating and detecting an ionized sample in terms of the mass-to-charge ratios, which is suitable for detecting molecules having a large mass such as protein. In a time-of-flight mass spectrometer, ions are generated in pulses on the surface of the sample and the generated ions are accelerated by an electric field in a vacuum. Since the velocity at which an ion flies varies depending on the mass-to-charge ratio of the ion, by measuring the time taken for an ion to fly a certain distance from when the ion is emitted from the sample to when the ion reaches a detector, the mass-to-charge ratio of the ion can be measured.
There are two-type of techniques of the imaging mass spectrometry technology, that is, scanning-type and projection-type techniques.
In the scanning-type, a fine region (depending on a beam diameter of a primary beam) on the sample is sequentially subjected to mass spectrometry, and the distribution of substances is reconstructed from results of mass spectrometry and positional information of the fine region.
In the projection-type technique, a large region of a sample is irradiated with a primary beam having a comparatively large irradiation region on the sample so as to ionize the sample, and a position/time sensitive detector is used to detect a time at which the generated ions reach the detector and a position on a detection surface of the detector where the ions reach. With this structure, a spatial distribution of substances included in the sample can be measured by simultaneously measuring the masses of detected ions and the positions of the ions on the surface of the sample.
A typical example of mass spectrometers is disclosed in Japanese Patent Laid-Open No. 2008-282726. In this mass spectrometer, ion beams are used and a bias potential is uniformly applied to a substrate. When ions are used as a primary beam, compared to the case in which a sample is irradiated with laser light, there is no need of use of a matrix, and secondary ions is easily uniformly generated. Thus, resolution in imaging is improved.
In related-art scanning-type time-of-flight mass spectrometers and projection-type time-of-flight mass spectrometers, a primary ion beam is often obliquely incident upon the surface of a sample. This structure is adopted in order to avoid interference of a primary ion irradiating system with an ion detection system that detects ions emitted from the sample.
The sample is irradiated with a primary ion beam pulsed with respect to time. The reason for this is to measure the time-of-flight of the secondary ions by generating the secondary ions in pulses.
A primary ion beam often spreads in a direction perpendicular to the beam direction. For this reason, when the primary ion beam is obliquely incident upon the surface of the sample, as illustrated in FIG. 1B, the distance between an ion source (not shown) and a sample 2 varies in accordance with a position on the surface of the sample 2.
As a result, the time taken for the primary ions emitted from the ion source in pulses to reach the surface of the sample 2 varies with the position on the surface of the sample 2.
Particularly in a projection-type time-of-flight mass spectrometer, a primary ion beam, with which a large region is irradiated, is used. That is, spreading of the primary ion beam in a direction perpendicular to the beam traveling direction is non-negligible. Thus, the above-described time variation causes a problem.
Also in a scanning-type time-of-flight mass spectrometer, in which such spreading of the primary ion beam is so small that the spreading is negligible, the distance between the ion source and the sample 2 varies in accordance with the position on the surface of the sample 2 when the position irradiated with the primary ion beam is moved due to scanning.
In the case where the distribution of substances in the sample is measured, the time when primary ions reach the surface of the sample 2 varies in accordance with the position because the position irradiated with the primary ion beam on the surface changes due to the movement of the primary ion beam.
In positions where the primary ions reach earlier, the secondary ions are generated on the surface of the sample earlier. In positions where the primary ions reach later, the secondary ions are generated on the surface of the sample later. As a result, time variation among times when the secondary ions are generated occurs in accordance with the position on the surface of the sample (referred to as “generation time variation” hereafter).
The generation time variation is part of errors in measurement of the time of flight of secondary ions, and accordingly, errors are observed in measured masses of the secondary ions.
For example, when a secondary ion is generated at a position where a primary ion reaches earlier than other positions on the surface of the sample, the time of flight of the secondary ion appears to be short. Thus, a smaller mass-to-charge ratio (m/z) is measured for the secondary ion. In contrast, when a secondary ion is generated at a position where a primary ion reaches later on the surface of the sample, the time of flight of the secondary ion appears to be long. Thus, a larger mass-to-charge ratio (m/z) is measured for the secondary ion.
Thus, there is a problem in that errors are observed in mass measurement of the secondary ions in accordance with the position on the surface of the sample.
In the time-of-flight mass spectrometer disclosed in Japanese Patent Laid-Open No. 2008-282726, although a bias voltage is uniformly applied to a sample, it is difficult for this mass spectrometer to suppress errors observed relating to the generation time variation of the secondary ions on the surface of a sample.
That is, in related-art time-of-flight mass spectrometers in which the primary ion beam is obliquely incident upon the surface of the sample, it is difficult to prevent time at which the primary ions reach the surface of the sample from varying. As a result, errors are observed in measurement of the time of flight of the secondary ions and in measurement of masses. Accordingly, there is a problem in that an accurate analysis is difficult.